Many studies examining a role for HLA in outcome to HIV-1 exposure and infection have been reported, but the associations have often been difficult to affirm in multiple cohorts. Nevertheless, the recurrent implication of certain haplotypes along with the quasi-species pattern of HIV-1 change in infected patients are strong indicators of HLA involvement in HIV-1 pathogenesis. We have typed the class I genes, HLA-A, -B, and -C, using DNA from about 1,000 HIV-1 seroconverters, and have just completed typing of about 1,500 seroprevalent individuals. Available clinical data indicates the AIDS defining illness (including Kaposi's sarcoma, pneumocystis pneumonia, Mycobacterium avium infection, and cytomegalovirus-associated retinitis)in each of these individuals. HLA class I alleles and haplotypes can now be tested for their potential effects on disease outcome after HIV-1 infection using both survival analyses in individuals whose seroconversion date is known, and also in categorical analysis using data from all individuals. We have previously demonstrated a highly significant association of HLA class I homozygosity with rapid progression to AIDS in both Caucasians and African Americans and we will determine whether zygosity also plays a role in determining AIDS-defining illness in these patients. Outcome to HIV-1 infection is dependent on a complex assortment of viral and host genetic factors. The contribution of HLA class I loci, particularly HLA-B locus, in regulating HIV-1 disease progression is the strongest among a dozen or so host genetic effects identified to date. The genetic influence of HLA class I on AIDS reflects the wealth of functional data that indicates the importance of MHC class I-restricted cytotoxic T cell (CTL) activity in controlling the virus. However, levels of CTL activity do not completely account for the extent of resistance to HIV-1 and additional branches of the immune system most certainly contribute to viral restriction. Natural killer (NK) cells participate in an early innate immune response against tumor- and virally-infected cells through a complex set of receptors that regulate inhibition and activation of NK cell activity (see Project number Z01 BC 10305-03 LGD). One group of NK receptors, the killer immunoglobulin-like receptors (KIR), recognize certain HLA class I molecules and thereby inhibit or activate NK cell responses. We hypothesized that HLA-B might play a role in the innate immune response by behaving as a ligand for the NK cell receptor KIR3DS1, which is thought to participate in activation of NK cells. We typed for the presence or absence of KIR3DS1 in over 1,000 HIV-1 seroconverters and tested for potential effects of this gene, the gene encoding its putative ligand (i.e. HLA-B), and a combination of both. The preliminary analysis indicates that the presence of KIR3DS1 in combination with HLA-B alleles encoding isoleucine at position 80 (HLA-BIle80) results in significantly delayed progression to AIDS and AIDS-related death. In the absence of KIR3DS1, the HLA-BIle80 alleles were not associated with any of the outcomes measured. Strikingly, KIR3DS1 in the absence of HLA-BIle80 was significantly associated with rapid progression to AIDS. Thus, the protective effect of KIR3DS1 and HLA-BIle80 appears to be synergistic and cannot be attributed to additive effects of these loci. An ongoing analysis of this data is underway. Hepatitis C virus (HCV) is the most common bloodborne infection in the United States with estimates of 4 million HCV-infected persons in the U.S. and 170 million worldwide. Viremia persists in 85% and is cleared in 15% of acutely-infected individuals. Some individuals with persistent infection will develop life-threatening complications of cirrhosis or hepatocellular carcinoma. We hypothesized that the HLA class I genes are predictors of outcome after HCV infection and to test the hypothesis we have completed typing of HLA class I on 231 clearance cases and 443 matched controls who have persistent infection. HLA-A*1101, B*57, and Cw*0102 were associated with viral clearance, whereas A*2301, and Cw*04 were associated with viral persistence. The Cw*04 effect on HCV persistence was the most significant among the associations observed and having two copies of the gene was more strongly associated with persistence than having one copy. The results provides justification for further studies of several HLA alleles for their role in HCV pathogenesis. DC-SIGN is a dendritic cell-specific ICAM-3 adhesion receptor that enhances HIV-1 infection of T cells in trans, indicating that it may play an important role in HIV-1 transmission from the site of entry to peripheral lymph nodes. However, these results are derived from in vitro analyses and there is no in vivo data to support a role for DC-SIGN in HIV pathogenesis. Given the functional activity of this molecule, we proposed that polymorphisms in the coding sequence or promoter region of this gene may possibly influence outcomes to HIV-1 infection. Screening of about 100 individuals for nucleotide variation indicated conservation of DC-SIGN coding sequences, but six common and 10 rare variants were identified in the region 2 Kb upstream of the ATG start codon. Six haplotypes with frequencies of >1% were identified. Preliminary analysis indicates that promoter region alleles containing the variant -336C is associated with susceptibility to parenteral (OR=2.11, p=0.0002), but not mucosal (OR=0.8, ns) infection. Additional samples are being typed and the potential effects of these variants in both infection and survival analyses will be tested. These epidemiologic data may provide data to support a role for DC-SIGN in vivo.